Transdermal Delivery System For Use With Basic Permeation Enhancers

Abstract

The present invention includes transdermal delivery systems having a polymeric active agent reservoir fabricated from an admixture of polyisobutylene and an insoluble hydrophilic polymer in powdered form, which provide numerous advantages in the transdermal delivery of active agents using basic enhancer compositions. For example, the systems of the invention provide for (1) increased permeation of the active agent through the skin, (2) an improved capability of extracting the active agent and enhancer from the transdermal systems, (3) enhanced structural integrity, (4) good chemical stability, (5) reduced phase separation, and (6) decreased cold flow.

1 . A transdermal delivery system for administering an active agent through the body surface, comprising:
 (a) a polymeric matrix that serves as both an active agent reservoir and a skin contact adhesive layer, wherein the matrix comprises a substantially homogeneous mixture of a polyisobutylene rubber and an insoluble hydrophilic polymer in the form of a powder having a particle size in the range of about 1 micron to 300 microns;   (b) a pharmaceutical formulation absorbed in the polymeric matrix which comprises a therapeutically effective amount of the active agent, an effective flux-enhancing amount of a basic permeation enhancing composition, and a pharmaceutically acceptable aqueous vehicle; and   (c) a backing layer laminated to the polymeric matrix that serves as the outer surface of the device use.   
     
     
         2 . The system of  claim 1 , wherein the polyisobutylene rubber:
 (a) has a molecular weight selected to provide the polymeric matrix with sufficient tack to ensure adhesion of the delivery system to the skin during active agent administration;   (b) is modified by admixture with an additive selected to provide the polymeric matrix with sufficient tack to ensure adhesion of the delivery system to the skin during active agent administration; or   (c) both (a) and (b).   
     
     
         3 . The system of  claim 2 , wherein the additive comprises a polybutene. 
     
     
         4 . The system of  claim 1 , wherein the polymeric matrix further includes at least one of: a water-swellable polymer in an amount sufficient to provide the polymeric matrix with sufficient tack to ensure adhesion of the delivery system to the skin during active agent administration; and an emulsifier. 
     
     
         5 . The system of  claim 4 , wherein the water-swellable polymer is a polyalkylene oxide and the emulsifier is a fatty acid or fatty alcohol. 
     
     
         6 . The system of  claim 1 , wherein the insoluble hydrophilic polymer has a particle size is in the range of about 10 microns to 200 microns. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The system of  claim 1 , wherein the insoluble hydrophilic polymer has a bulk density in the range of approximately 0.1 g/cm 3  to 0.5 g/cm 3 . 
     
     
         10 . The system of  claim 9 , wherein the insoluble hydrophilic polymer has a bulk density in the range of approximately 0.2 g/cm 3  to 0.4 g/cm 3 . 
     
     
         11 . The system of  claim 1 , wherein the insoluble hydrophilic polymer is lightly crosslinked. 
     
     
         12 . The system of  claim 1 , wherein the insoluble hydrophilic polymer is not crosslinked. 
     
     
         13 . The system of  claim 1 , wherein the insoluble hydrophilic polymer comprises a mixture of crosslinked and uncrosslinked polymer. 
     
     
         14 . The system of  claim 1 , wherein the insoluble hydrophilic polymer is selected from: polyvinylpolypyrrolidone; poly(N-vinyl-2-caprolactam); poly(N-vinyl-2-valerolactam); carboxymethylcellulose sodium; poly(acrylamide-acrylic acid) sodium salt of starch; and sodium polyacrylate. 
     
     
         15 - 21 . (canceled) 
     
     
         22 . The system of claim  21 , wherein the inorganic hydroxide is selected from ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and combinations thereof, and the nitrogenous base is selected from urea and amino alcohols. 
     
     
         23 . The system of  claim 22 , wherein the inorganic hydroxide is an alkali metal hydroxide and the nitrogenous base is an amino alcohol. 
     
     
         24 . The system of  claim 23 , wherein the amino alcohol is of the structural formula NR 1 R 2 R 3  wherein R 1  is hydroxy-substituted hydrocarbyl, and R 2  and R 3  are selected from H, hydrocarbyl, and hydroxy-substituted hydrocarbyl. 
     
     
         25 . The system of  claim 24 , wherein R 1  is C 1 -C 12  alkyl substituted with 1 to 12 hydroxyl groups, and R 2  and R 3  are selected from H, C 1 -C 12  alkyl, and C 1 -C 12  alkyl substituted with 1 to 12 hydroxyl groups. 
     
     
         26 . The system of  claim 25 , wherein R 1  is C 1 -C 6  alkyl substituted with 1 to 5 hydroxyl groups, and R 2  and R 3  are selected from H, C 1 -C 6  alkyl, and C 1 -C 6  alkyl substituted with 1 to 5 hydroxyl groups. 
     
     
         27 . The system of  claim 26 , wherein R 1 , R 2 , and R 3  are —CH 2 CH 2 OH, such that the amino alcohol is triethanolamine. 
     
     
         28 . The system of  claim 26 , wherein R 1  and R 2  are —CH 2 CH 2 OH, and R 3  is H, such that the amino alcohol is diethanolamine. 
     
     
         29 . The system of  claim 26 , wherein R 1  is —CH 2 —[CH(OH)] 4  —CH 2 OH, R 2  is CH 3 , and R 3  is H, such that the amino alcohol is diethanolamine. 
     
     
         30 . The system of  claim 1 , wherein the apparent aqueous solubility of the active agent increases with increasing pH. 
     
     
         31 . The system of  claim 30 , wherein the apparent aqueous solubility of the active agent is greater than 5 mg/ml at a pH of 8.0, when measured at 25° C. 
     
     
         32 . The system of  claim 31 , wherein the apparent aqueous solubility of the active agent is greater than 10 mg/ml at a pH of 9.0, when measured at 25° C. 
     
     
         33 . The system of  claim 1 , wherein the active agent is ionizable. 
     
     
         34 . The system of  claim 33 , wherein the active agent is an acidic agent in the form of a basic addition salt. 
     
     
         35 . The system of  claim 1 , wherein the active agent is selected from analgesic agents, anesthetic agents, anti-anginal agents, antiarthritic agents, anti-arrhythmic agents, antiasthmatic agents, antibiotic agents, anticancer agents, anticholinergic agents, anticoagulants, anticonvulsants, antidepressants, antidiabetic agents, antifungal agents, antiglaucoma agents; antigout agents, antihelminthic agents, antihistamines, antihyperlipidemic agents, antihypertensive agents, antiinflammatory agents, antimalarial agents, antimigraine agents, antimuscarinic agents, antinauseants, anti-obesity agents, anti-osteoporosis agents, antipanic agents; antiparkinsonism agents, antiprotozoal agents, antipruritics, antipsychotic agents, antipyretics, antitubercular agents, antitussive agents, antiulcer agents, antiviral agents, anxiolytics, appetite suppressants, calcium channel blockers, cardiac inotropic agents, beta- blockers, bone density regulators, central nervous system stimulants, cognition enhancers, corticosteroids, decongestants, diuretics, gastrointestinal agents, genetic materials, hormonolytics, hypnotics, hypoglycemic agents, immunosuppressants, keratolytics, leukotriene inhibitors, macrolides, mitotic inhibitors, muscle relaxants, narcotic antagonists, neuroleptic agents, nicotine, parasympatholytic agents, sedatives, sex hormones, sympathomimetic agents, tocolytics, tranquilizers, vasodilators, vitamins, and combinations thereof. 
     
     
         36 . The system of  claim 1 , wherein the backing layer is occlusive. 
     
     
         37 . An active agent reservoir comprising:
 (a) a polymeric matrix that comprises a substantially homogeneous mixture of a polyisobutylene rubber and an insoluble hydrophilic polymer in the form of a powder having a particle size in the range of approximately 1 micron to 300 microns;   (b) a pharmaceutical formulation absorbed in the polymeric matrix which comprises a therapeutically effective amount of an active agent, an effective flux-enhancing amount of a basic permeation enhancing composition, and a pharmaceutically acceptable aqueous vehicle.   
     
     
         38 . A method for transdermally administering an active agent, which comprises affixing a transdermal delivery system to a localized region of a human patient's body surface such that a body surface-delivery system interface is formed, wherein the system comprises:
 (a) a polymeric matrix that serves as both an active agent reservoir and a skin contact adhesive layer, wherein the matrix comprises a substantially homogeneous mixture of a polyisobutylene rubber and an insoluble hydrophilic polymer in the form of a powder having a particle size in the range of approximately 1 micron to 300 microns;   (b) a pharmaceutical formulation absorbed in the polymeric matrix which comprises a therapeutically effective amount of the active agent, an effective flux-enhancing amount of a basic permeation enhancing composition, and a pharmaceutically acceptable aqueous vehicle; and   (c) a backing layer laminated to the polymeric matrix that serves as the outer surface of the device use.   
     
     
         39 - 77 . (canceled)